Essential Function of Ghrelin in Chronic Starvation Essential... · Essential Function of Ghrelin...
Transcript of Essential Function of Ghrelin in Chronic Starvation Essential... · Essential Function of Ghrelin...
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Essential Function of Ghrelin
in Chronic Starvation
Guosheng Liang
UT Southwestern Medical Center at Dallas
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Ghrelin: An Acylated Peptide
E-2102.ppt
Kojima & Kangawa1999
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Ghrelin O-Acyltransferase (GOAT)
• Identified in our lab by combined approach of
bioinformatics and expression testing of candidate
cDNAs in cultured endocrine cells.
• Candidate cDNAs: Family of 16 Membrane-Bound O-
Acyltransferases (MBOATs) that transfer fatty acyl groups
to lipids or proteins (ACAT, DGAT, Porcupine)
• MBOAT4 transfers octanoate from octanoyl-CoA to
serine-3 of Proghrelin
• Eli Lilly group also identified MBOAT4 as the
acytransferase that octanoylates ghrelin in the same year
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Processing of Preproghrelin
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Processing of Preproghrelin in Endocrine Cell Lines
AtT-20: Mouse pituitary tumor cell
INS-1: Rat insulinoma cell line
MIN-6: Mouse insulinoma cell line
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E-2016.ppt
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E-2015.ppt
Hydropathy Plot of
Ghrelin O-Acyltranferase (GOAT)
E-2015.ppt
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Expression of GOAT in Mouse Tissues
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Co-localization of GOAT with Ghrelin
in Gastric Mucosa
E-2134.ppt
Ghrelin GOAT
I. Sakata, J. Yang, J. Elmquist, & J. Zigman, 2008
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E-2383-2.ppt
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Body Weights on Different Diets
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Metabolic Response to Food Deprivation
in GOAT -/- Mice
Each mouse fed 40% of its daily food intake
for 7-9 days
Food supplied at 6 pm each day and
eaten within 1 hr
Blood glucose measured every day at 5:30 pm
(22.5 hr after eating and 30 min before next feeding)
E-2539.ppt
60% Calorie Restriction
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Body Weight and Fat Mass in WT and Goat -/- Mice
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Calorie-restricted Goat -/- Mice Exhibit
Severe Hypoglycemia Before Next Meal
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Blo
od
Glu
co
se
at
5:3
0 p
m (
mg
/dl)
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Plasma Ghrelin and Growth Hormone in ad lib Fed or
Calorie Restricted WT and Goat -/- Mice
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Response to Day-Long Starvation After 7 days
of Calorie Restriction in Goat-/- Mice
n = 4 mice
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n = 4 mice
Preproghrelin-/- Mice Show Same Defect
as Goat-/- Mice
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Prevention of Hypoglycemia by Infusion of
Ghrelin or Growth Hormone
CalorieRestriction
AgentOsmotic
Layer
SemipermeableMembrane
ImpermeableReservoir Flow
Moderator
E-2540.ppt
0 2 4 6
Ghrelinor GH
8
Days
Flow rate – 1.2 ml hr/Ghrelin – 30 mg 24 hr/GH – 15 mg 24 hr/
3
Osmotic Minipump
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Prevention of Hypoglycemia by Infusion of Ghrelin
Day 7
5:30 pm
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Response to Infusion of Growth Hormone
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How Does Starvation-Induced
Hypoglycemia Stimulate
Ghrelin Secretion?
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Generation of Transgenic Ghrelin-SV40-T Mice
E-2420 slide 1.ppt
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Markedly Elevated Ghrelin Levels in
Ghrelinoma-bearing Mice
E-2420 slide 3 ppt
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Norepinephrine Stimulates Ghrelin Secretion
in Ghrelinoma PG-1 Cells
E-2419-2 slide.ppt
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Stimulation of Ghrelin Secretion in PG-1 Cells
by b-Adrenergic Agents
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Relative Amounts of mRNAs in PG-1 Cells and SG-1 Cells
mRNAStomach
WT
Stomach
Ghrelinoma
PG-1
Cells
SG-1
Cells
Preproghrelin
GOAT
Prohormone
Convertase 1/3
1.0 (21)*
1.0 (29)
7.1
8.3
5.5
13.8
1.0 (28) 36
7.7
13.4
188231
*Threshold value for RT-PCR (cycles)
E-2525.ppt
Fold-increase
b1 Receptor
b2 Receptor
1.0 (33)
1.0 (29)
138
1.1
416
0.5
138
0.1
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Suppression of Ghrelin Secretion in Fasted WT Mice
by Reserpine and Atenolol
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Summary: Metabolic Response to Chronic Starvation
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How Ghrelin Releases Growth Hormone
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Summary
One Essential Function of Ghrelin Is
to Maintain Blood Sugar by Stimulating
Growth Hormone Release in Times of Famine
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Acknowledgements
Tong-Jin Zhao
Robert Li
Jing Yang
Michael Brown and Joseph Goldstein
Ichiro Sakata and Jeff Zigman
Ghrelin-SV40 Tg
Regeneron Pharmaceuticals
Tamas Horvath
GOAT and Ghrelin Knockout